Home Medicine Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
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Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels

  • Huan Li , Xiaomin Xie EMAIL logo , Li Zhang , Yanting He , Huili Liu , Dan Qiang , Guirong Bai , Ling Li and Yanpan Tang
Published/Copyright: March 1, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Vitamin D is a fat-soluble vitamin with multiple functions. However, the metabolism of people with different vitamin D concentrations is still unclear. Herein, we collected clinical data and analysed the serum metabolome of people with 25-hydroxyvitamin D (25[OH]D) ≥40 ng/mL (A), 30 ng/mL ≤25(OH)D <40 ng/mL (B) and 25(OH)D <30 ng/mL (C) by the ultra-high-performance liquid chromatography-tandem mass spectrometry method. We found that haemoglobin A1c, fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance and thioredoxin interaction protein were enhanced, while HOMA-β was reduced with the decrease of 25(OH)D concentration. In addition, people in the C group were diagnosed with prediabetes or diabetes. Metabolomics analysis showed that seven, thirty-four and nine differential metabolites were identified in the groups B vs A, C vs A and C vs B, respectively. Metabolites associated with cholesterol metabolism and bile acid biosynthesis, such as 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid, N-arachidene glycine and d-mannose 6-phosphate, were significantly upregulated in the C group compared with the A or B groups. In conclusion, the disorder of vitamin D metabolism may be related to cholesterol metabolism and bile acid biosynthesis. This study provided a basis for exploring the possible mechanism leading to abnormal vitamin D metabolism.

Keywords: metabolomics; ultra-high-performance liquid chromatography-tandem mass spectrometry; vitamin D; cholesterol metabolism

1 Introduction

Vitamin D is a fat-soluble vitamin and performs various functions in the body. Vitamin D is present in the body in two primary forms, and It is mainly produced in the skin following exposure to ultraviolet irradiation. The vitamin D is also absorbed via food intake. In the liver, vitamin D is hydroxylated by the enzyme 25-hydroxylase to form 25-hydroxyvitamin D [25(OH)D], which is subsequently hydroxylated to 1α,25-dihydroxyvitamin D [1α,25(OH)2D] [1]. Active vitamin D exerts its biological function by combining it with the vitamin D receptor (VDR). The vitamin D status is evaluated by detecting 25(OH)D serum concentration. In 2011, the Endocrine Society defined 25(OH)D less than 20 ng/mL as vitamin D deficiency, 25(OH)D more than 30 ng/mL as vitamin D sufficiency and 25(OH)D between 20 and 30 ng/mL as vitamin D insufficiency [2]. Studies have shown that high and low vitamin D levels are associated with various diseases, including chronic complications of type 2 diabetes, non-alcoholic fatty liver disease, obesity, anxiety and depression [3,4,5,6]. Excessive vitamin D may result in hypercalcaemia, hypercalciuria and hyperphosphatemia [7]. Vitamin D deficiency is presumed to participate in the pathogenesis of metabolic syndromes by promoting inflammatory response, increasing insulin resistance, promoting adipocyte differentiation and affecting lipid metabolism [8]. Some studies have indicated that vitamin D deficiency is related to type I and type II diabetes [9,10]. Interestingly, 1α,25(OH)2D plays a crucial role in glucose homeostasis through various mechanisms. It not only boosts the insulin sensitivity of target cells (skeletal muscle, liver and adipose tissue), but also directly protects β cells from harmful immune attacks [11,12]. However, the metabolic characteristics of people with different vitamin D levels are unclear.

Metabolomics technology combines analytical chemistry based on physics, stoichiometry based on mathematical computational modelling and life science based on biochemistry. The metabolomic techniques frequently used mainly include nuclear magnetic resonance, liquid chromatography and liquid chromatography-tandem mass spectrometry (LC-MS/MS) [13]. LC-MS/MS has been widely employed due to its advantages of high sensitivity, strong specificity and simple sample treatment [14]. Ultra-high-performance LC-MS/MS (UPLC-MS/MS) has high separation efficiency and sufficient resolution. UPLC-MS/MS is a powerful method for determining metabolomics divergence derived from disease-related changes [15,16]. Therefore, UPLC-MS/MS could help analyse the metabolomics of people with different vitamin D levels.

In the present study, we aimed to investigate the metabolomic changes in people with different vitamin D levels. We assessed the clinical characteristics and the metabolites measured with UPLC-MS/MS in a cohort stratified on the full range of vitamin D levels. Moreover, we explored the possible mechanism leading to abnormal vitamin D metabolism.

2 Materials and methods

2.1 Subjects

Forty subjects were recruited from the physical examination Centre of The First People’s Hospital of Yinchuan. There were 22 males and 18 females, aged 27 to 57. According to 25(OH)D levels, they were divided into three groups: A, 15 people with 25(OH)D ≥40 ng/mL; B, 15 people with 25(OH)D between 30–40 ng/mL; C, 10 people with 25(OH)D <30 ng/mL. The disorder of vitamin D metabolism was defined as 25(OH)VD <30 ng/mL. None of the people received any lifestyle interventions or medications. Exclusion criteria are as follows: (a) prior diagnosis of prediabetes and diabetes; (b) patients with kidney, liver, or cancer; (c) patients with acute/chronic inflammatory disease; (d) patients with a history of cardiovascular and cerebrovascular diseases; (e) patients with thyroid dysfunction; (f) patients with blood disease; (g) people with alcohol or drug abuse or smoking; (h) women with hormone replacements; (i) patients who had taken vitamin D supplements in the last three months.

  1. Ethical approval: This study was approved by the Ethics Committee of The First People’s Hospital of Yinchuan.

  2. Informed consent statement: Written informed consent was obtained from all the participants.

2.2 General measurements

All subjects were given a unified questionnaire, and general data were collected, including gender, age, smoking history, height, weight, waist circumference (WC), hip circumference, body index (BMI), waist-hip ratio (WHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). All subjects were sampled from August 2020 to November 2020, and peripheral venous blood was collected after fasting for 8–12 h. The serum samples of all subjects were stored at −80°C. Fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), uric acid (UA), urea, creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) were measured using Beckman Coulter automatic biochemical analyser AU5821. The concentration of fasting insulin (FINS), haemoglobin A1c (HbA1c), 25(OH)D and thioredoxin-interacting protein (TXNIP) was determined by ELISA. Homeostasis model assessment of insulin resistance (HOMA-IR) = FBG*FINS/22.5. Homeostasis model assessment-β (HOMA-β) = 20*FINS/(FBG-3.5).

2.3 UPLC-MS/MS

A UPLC HSS T3 column (1.8 μm particle size, 2.1 mm × 100 mm) served as the stationary phase for the chromatographic isolation. The samples were isolated using acetonitrile and water (0.1% formic acid) through gradient elution with a flow rate of 0.4 mL/min. The gradient elution was as follows: 0 min, water/acetonitrile (95:5 V/V); 11.0 min, water/acetonitrile (10:90 V/V); 12.0 min, water/acetonitrile (10:90 V/V); 12.1 min, water/acetonitrile (95:5 V/V) and 14.0 min, water/acetonitrile (95:5 V/V). The column temperature was 40°C, and the injection volume was 2 μL.

MS conditions were set as follows: Electrospray ionisation temperature was set at 500°C. MS voltage was 5,500 V positive and −4,500 V negative. Ion source gas I (GS I) was 55 psi. Gas II (GS II) was 60 psi. The curtain gas was 25 psi. The collision-activated ionization parameter was set to high. Each ion pair was scanned in a triple quadrupole based on the optimized declustering potential and collision energy.

The frozen blood was resuscitated at room temperature, and 1 mL of 80% methanol internal standard extraction agent was added to the samples. The samples were subjected to liquid nitrogen, thawing and vortex three times and centrifuged at 12,000 rpm at 4°C for 10 min. After centrifugation, 200 µL of supernatant was taken into the inner tube of the corresponding bottle for UPLC-MS/MS analysis.

2.4 Metabolomics data analysis

The mass spectrum data were processed using the Analyst 1.6.3 software. Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were carried out using ropls of R package 3.3.2. OPLS-DA model parameters, R2X, R2Y and Q2, were applied to evaluate model validity. The metabolites were analysed statistically in line with variable importance for the projection (VIP), P-value of t-test and fold change (FC). FC ≥ 2, P ≤ 0.05 and VIP ≥ 1 were used as criteria for the preliminary screening of metabolites between groups and combined with the Venn diagram, differential metabolites between groups were further screened. MetaboAnalyst 5.0 software (https://www.metaboanalyst.ca/) combined with the Kyoto Encyclopedia of Genes and Genomes (KEGG) and HMDB database was employed to analyse the metabolic pathways of the screened differential metabolites. The sequencing and bioinformatics analysis was performed by Beijing Biomarker Technology.

2.5 Statistical analysis

The data were analysed using SPSS 26.0 and presented as the mean ± standard deviation (SD). The t-test was utilised to analyse the difference between the two groups, and one-way analysis of variance (ANOVA) was employed to evaluate the statistical significance of exceeding two groups. P < 0.05 was considered statistically significant.

3 Results

3.1 Clinical characteristics of subjects with different vitamin D levels

A total of 15 people with 25(OH)D ≥40 ng/mL (group A), 15 people with 25(OH)D between 30–40 ng/mL (group B) and 10 people with 25(OH)D <30 ng/mL (group C) were enrolled in this study. The clinical information of the subjects recruited is shown in Table 1. There was no remarkable difference among the three groups in age, SBP, DBP, BMI, WC, WHR, TG, TC, HDL, LDL, ALT, AST, GGT, urea, Cr and UA. The 25(OH)D concentration decrease significantly promoted the levels of HbA1c, FBG, FINS, HOMA-IR and TXNIP and inhibited HOMA-β. The levels of HbA1c, FBG, FINS, HOMA-IR and TXNIP were the highest, while HOMA-β was the lowest in the serum of people with 25(OH)D <30 ng/mL. However, the opposite results were observed in the serum of people with 25(OH)D ≥40 ng/mL. The results indicated that vitamin D deficiency led to FBG elevation and insulin resistance.

Table 1

Demographic and clinical information of participants

Characteristics A (n = 15) B (n = 15) C (n = 10) F P value
Age (year) 44.93 ± 8.67 43.47 ± 6.66 44.90 ± 8.72 0.155 0.857
SBP (mmHg) 118.40 ± 7.42 118.40 ± 10.11 121.90 ± 10.71 0.526 0.596
DBP (mmHg) 75.00 ± 9.35 73.07 ± 8.15 75.00 ± 6.13 0.26 0.772
BMI (kg/m2) 23.90 ± 3.60 23.42 ± 2.30 25.61 ± 3.75 1.455 0.246
WC (cm) 82.07 ± 10.07 78.93 ± 6.72 88.00 ± 9.31 3.237 0.051
WHR (cm/cm) 0.86 ± 0.07 0.82 ± 0.05 0.88 ± 0.03 3.001 0.062
TG (mmol/L) 2.01 ± 1.19 2.77 ± 3.98 2.29 ± 0.97 0.173 0.842
TC (mmol/L) 4.92 ± 1.07 5.35 ± 2.42 5.60 ± 1.29 0.49 0.617
HDL (mmol/L) 1.36 ± 0.30 1.33 ± 0.27 1.29 ± 0.17 0.233 0.793
LDL (mmol/L) 2.71 ± 0.78 3.33 ± 1.73 3.33 ± 0.96 1.224 0.306
ALT (μmol/L) 23.10 ± 7.13 23.55 ± 6.44 25.78 ± 4.53 0.724 0.501
AST (μmol/L) 25.57 ± 6.04 23.55 ± 6.44 25.78 ± 4.53 0.606 0.551
GGT (μ/L) 32.44 ± 17.06 33.72 ± 17.63 62.94 ± 76.03 1.379 0.264
UREA (mmol/L) 4.68 ± 0.99 4.50 ± 1.16 4.81 ± 1.15 0.252 0.779
Cr (mmol/L) 64.05 ± 12.05 58.65 ± 13.34 61.26 ± 12.56 0.796 0.459
UA (mmol/L) 334.61 ± 92.88 281.70 ± 95.99 309.43 ± 96.08 0.451 0.718
HbA1c (ng/mL) 172.17 ± 31.88 210.56 ± 30.34 247.04 ± 19.76 20.721 <0.01
FBG (mmol/L) 5.44 ± 0.66 7.00 ± 2.98 10.46 ± 3.10 16.477 <0.01
FINS (mIU/L) 4.99 ± 0.69 5.75 ± 0.71 6.43 ± 0.62 13.66 <0.01
HOMA-IR 1.22 ± 0.30 1.84 ± 1.00 3.04 ± 1.08 18.212 <0.01
HOMA-β 56.62 ± 18.83 44.48 ± 18.90 22.97 ± 11.67 14.912 <0.01
25(OH)D (ng/mL) 49.12 ± 6.64 36.10 ± 3.72 22.21 ± 3.83 86.09 <0.01
TXNIP (ng/mL) 3.45 ± 0.81 4.59 ± 1.13 6.11 ± 1.16 20.097 <0.01

The data are represented as the mean ± SD. The one-way ANOVA (F-test) was utilised to determine differences in various indicators among A, B and C groups. F and P represented the results of ANOVA analysis among all the groups. A group: people with 25(OH)D ≥40 ng/mL; B group: people with 30 ng/mL ≤ 25(OH)D <40 ng/mL; C group: people with 25(OH)D <30 ng/mL; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; WC: waist circumference; WHR: waist-hip rate; TG: triglyceride; TC: total cholesterol; HDL: high-density lipoprotein; LDL: low-density lipoprotein; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; Cr: creatinine; UA: uric acid; HbA1c: haemoglobin A1c; FBG: fasting blood glucose; FINS: fasting insulin; HOMA-IR: homeostasis model assessment of insulin resistance; HOMA-β: homeostasis model assessment-β; 25(OH)D: 25-hydroxyvitamin D; TXNIP: thioredoxin interaction protein.

3.2 Analysis of abnormal glucose metabolism in individuals with low vitamin D

The analysis of abnormal glucose metabolism is shown in Table 2. In the A group, people with less than 5.6 mmol/L of FBG accounted for 53.33%, and people with 5.6–7 mmol/L of FBG accounted for 46.67%. In the B group, people with less than 5.6 mmol/L of FBG accounted for 13.33%, people with 5.6–7 mmol/L of FBG accounted for 66.67%, and people with more than 7 mmol/L of FBG accounted for 20%. In the C group, people with 5.6–7 mmol/L of FBG accounted for 30%, people with more than 7 mmol/L of FBG accounted for 70%. There were statistically significant differences among the three groups. Overall, 46.67% of people with 25(OH)D ≥40 ng/mL were diagnosed with prediabetes, 86.67% of people with 30–40 ng/mL of 25(OH)D were diagnosed with prediabetes or diabetes, and all people with 25 (OH)D <30 ng/mL were diagnosed with prediabetes or diabetes. Together, vitamin D deficiency contributes to abnormal glucose metabolism.

Table 2

The proportion of abnormal glucose metabolism at different 25(OH)D levels

group n FBG <5.6 mmol/L (%) 5.6 mmol/L ≤ FBG <7.0 mmol/L (%) FBG ≥7.0 mmol/L (%) χ 2 P
A 15 8 (53.33%) 7 (46.67%) 0 (0.00%)
B 15 2 (13.33%) 10 (66.67%) 3 (20.00%) 21.80 <0.001
C 10 0 (0.00%) 3 (30.00%) 7 (70.00%)

3.3 Multivariate analysis of serum metabolites

PCA is an unsupervised analysis method employed to observe the overall distribution trend among samples. The B and A groups were mostly overlapping and isolated in part, indicating that the serum components separation effect of the two groups was not very remarkable (Figure 1a). Similarly, the C vs A and C vs B groups showed the same results (Figure 1b and c). However, given the complexity of metabolomics, PCA analysis may not be capable of differentiating samples of different groups. Thus, to optimise the difference, OPLS-DA was performed. OPLS-DA is a supervised pattern recognition method which can reduce the differences within samples and more accurately characterise the characteristics between samples. OPLS-DA models showed apparent isolation of the metabolic profiles in B vs A, C vs A and C vs B groups (Figure 2a–c). R2Y values in the B vs A, C vs A and C vs B groups were 0.981, 0.987 and 0.989, respectively, suggesting that the model has a good distinction between the samples and that the samples within the same group are highly aggregated. OPLS-DA permutation verification showed that the original R2 and Q2 of the three groups were greater than the corresponding values after Y substitution, suggesting that the three groups were not over-fitted and could be used for the subsequent identification of metabolites. PCA and OPLS-DA score plots revealed a remarkable separation trend in serum comparison groups, indicating that vitamin D affected metabolic profiles.

Figure 1 PCA score plots of serum samples from the A, B and C groups. (a) PCA score plots in the B vs A group. (b) PCA score plots in the C vs A group. (c) PCA score plots in the C vs B group. A: people with 25-hydroxyvitamin D (25(OH)D) ≥40 ng/mL; B: people with 30 ng/mL ≤ 25(OH)D <40 ng/mL; C: people with 25(OH)D <30 ng/mL.
Figure 1

PCA score plots of serum samples from the A, B and C groups. (a) PCA score plots in the B vs A group. (b) PCA score plots in the C vs A group. (c) PCA score plots in the C vs B group. A: people with 25-hydroxyvitamin D (25(OH)D) ≥40 ng/mL; B: people with 30 ng/mL ≤ 25(OH)D <40 ng/mL; C: people with 25(OH)D <30 ng/mL.

Figure 2 OPLS-DA score plots and OPLS-DA permutation test of serum metabolic profiling. (a) OPLS-DA score plots and OPLS-DA permutation test in B vs A. (b) OPLS-DA score plots and OPLS-DA permutation test in C vs A. (c) OPLS-DA score plots and OPLS-DA permutation test in C vs B.
Figure 2

OPLS-DA score plots and OPLS-DA permutation test of serum metabolic profiling. (a) OPLS-DA score plots and OPLS-DA permutation test in B vs A. (b) OPLS-DA score plots and OPLS-DA permutation test in C vs A. (c) OPLS-DA score plots and OPLS-DA permutation test in C vs B.

3.4 Identification of potential metabolites related to vitamin D

The VIP and P values were used to reveal the importance of metabolites. Differential metabolites were screened based on the standard with VIP > 1 and P < 0.05. Of 38 differential metabolites, seven, 34, and nine were significantly altered in the B vs A, C vs A and C vs B groups, respectively (Figure 3a, Table 3). Compared with the A group, two metabolites were upregulated in the B group, including hexanoyl glycine and 7-ketodeoxycholic acid, while five were downregulated, including urocanic acid, dl-stachydrine, stachydrine, cyclopentylglycine and 1-methylpiperidine-2-carboxylic acid (Figure 3b). Compared with the A group, 27 metabolites were upregulated in the C group, including 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid, d-fructose 6-phosphate-disodium salt, and d-mannose 6-phosphate, while seven metabolites were downregulated, including guanine, 2-hydroxy-6-aminopurine, dl-stachydrine, stachydrine and 1-methylpiperidine-2-carboxylic acid (Figure 3c). Compared with the B group, six metabolites were upregulated in the C group, including N-arachidene glycine, 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid, d-mannose 6-phosphate and 2-furoylglycine, while three metabolites were downregulated, including Gly-Val, 2-hydroxy-6-aminopurine, and guanine (Figure 3d). Interestingly, there were five common upregulated metabolites and two common downregulated metabolites between the C vs A and C vs B groups (Figure 3e). N-arachidene glycine, 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid and d-mannose 6-phosphate were upregulated, while 2-hydroxy-6-aminopurine and guanine were downregulated in the C group compared with the A or B groups (Table 3).

Figure 3 Analyses of differential metabolites in people with different concentrations of vitamin D. (a) The number of differentially upregulated and downregulated metabolites in B vs A, C vs A, and C vs B groups. (b) The heatmap of the metabolites in the B vs A group. (c) The heatmap of the metabolites in the C vs A group. (d) The heatmap of the metabolites in the C vs B group. (e) Venn diagram comparison of upregulated and downregulated metabolites between the C vs A and C vs B groups.
Figure 3

Analyses of differential metabolites in people with different concentrations of vitamin D. (a) The number of differentially upregulated and downregulated metabolites in B vs A, C vs A, and C vs B groups. (b) The heatmap of the metabolites in the B vs A group. (c) The heatmap of the metabolites in the C vs A group. (d) The heatmap of the metabolites in the C vs B group. (e) Venn diagram comparison of upregulated and downregulated metabolites between the C vs A and C vs B groups.

Table 3

Identification results of differential metabolites in B vs A, C vs A, and C vs B groups in serum

B vs A Name A_Mean B_Mean Fold_change log2FC P value VIP Regulated
Hexanoyl glycine 1.31 × 10−6 2.63 × 10−6 2.005967 0.844079 0.040607 1.905295 Up
7-Ketodeoxycholic acid 3.86 × 10−7 9.76 × 10−7 2.529795 1.389847 0.033554 1.98678 Up
Urocanic acid 1.82 × 10−5 8.47 × 10−6 0.46546 −0.98821 0.013973 2.055689 Down
dl-Stachydrine 0.000224 9.33 × 10−5 0.41736 −1.62124 0.037106 1.935163 Down
Stachydrine 0.001707 0.000579 0.339247 −1.44771 0.006879 2.3834 Down
Cyclopentylglycine 0.00018 8.63 × 10−5 0.480418 −0.94127 0.019105 2.125388 Down
1-Methylpiperidine-2-carboxylic acid 0.00018 8.63 × 10−5 0.480418 −0.94127 0.019105 2.125388 Down
C vs A Name A_Mean C_Mean Fold_change log2FC P value VIP Regulated
Hexanoyl glycine 1.31 × 10−6 2.82 × 10−6 2.151301 1.161114 0.007712 1.692944 Up
1,5-Anhydro-d-glucitol 1.71 × 10−5 3.77 × 10−5 2.200946 1.230686 0.039567 1.378615 Up
d-Glucose 9.78 × 10−6 1.96 × 10−5 2.001923 0.970512 0.001199 2.06755 Up
d-Mannose 9.78 × 10−6 1.96 × 10−5 2.001923 0.970512 0.001199 2.06755 Up
l-Fucose 1.71 × 10−5 3.77 × 10−5 2.200946 1.230686 0.039567 1.378615 Up
l-Rhamnose 1.71 × 10−5 3.77 × 10−5 2.200946 1.230686 0.039567 1.378615 Up
d-Glucoronic acid 7.13 × 10−6 1.75 × 10−5 2.460647 1.27646 0.00165 2.084885 Up
FFA(20:2) 1.18 × 10−6 2.36 × 10−6 2.00392 1.051267 0.001095 1.93024 Up
N6-Succinyl adenosine 1.18 × 10−6 2.44 × 10−6 2.074618 1.116866 0.001011 1.987407 Up
d-Fructose 6-phosphate-disodium salt 2.89 × 10−6 9.52 × 10−6 3.297107 1.45351 0.017558 1.666147 Up
Hydroxyphenyllactic acid 3.99 × 10−6 8.15 × 10−6 2.042949 1.235163 0.003343 1.714463 Up
d-Malic acid 1.8 × 10−6 4 × 10−6 2.226528 1.228234 0.002488 1.850066 Up
Hexadecanedioic acid 0.000104 0.000219 2.101325 1.139583 0.026595 1.460663 Up
Myoinositol 9.78 × 10−6 1.96 × 10−5 2.001923 0.970512 0.001199 2.06755 Up
N-Arachidene glycine 6.95 × 10−7 1.72 × 10−6 2.474231 1.256188 0.007601 1.818215 Up
7-Ketolithocholic acid 2.05 × 10−5 0.000211 10.33455 2.534241 0.016816 1.79233 Up
1,6-Anhydro-β-d-glucose 2.2 × 10−6 5.55 × 10−6 2.524028 1.228959 0.003908 1.913047 Up
12-Ketolithocholic acid 2.05 × 10−5 0.000211 10.33455 2.534241 0.016816 1.79233 Up
Apocholic acid 2.05 × 10−5 0.000211 10.33455 2.534241 0.016816 1.79233 Up
d-Mannose 6-phosphate 5.2 × 10−6 1.44 × 10−5 2.769348 1.285293 0.011309 1.708365 Up
12-Hydroxyoctadecanoic acid 6.16 × 10−6 1.44 × 10−5 2.344905 1.189824 0.008935 1.856682 Up
d-Galacturonic Acid 7.13 × 10−6 1.75 × 10−5 2.460647 1.27646 0.00165 2.084885 Up
d-Tagatose 9.78 × 10−6 1.96 × 10−5 2.001923 0.970512 0.001199 2.06755 Up
3-Hydroxy-tetradecanoic acid 2.64 × 10−5 5.55 × 10−5 2.102486 1.183012 0.000731 1.953677 Up
d-Allose 9.78 × 10−6 1.96 × 10−5 2.001923 0.970512 0.001199 2.06755 Up
Kojibiose 2.1 × 10−5 5.83 × 10−5 2.783261 1.278691 0.019954 1.563984 Up
alpha-d-Glucopyranoside, beta-d-fructofuranosyl 7.07 × 10−6 1.72 × 10−5 2.426247 1.217379 0.027871 1.445197 Up
FFA(15:1) 0.000521 5.16 × 10−5 0.098985 −2.38714 0.002171 1.516013 Down
2-Hydroxy-6-aminopurine 3.14 × 10−6 8.59 × 10−7 0.273076 −2.29488 0.003089 1.397046 Down
dl-Stachydrine 0.000224 7.02 × 10−5 0.313853 −1.66445 0.00328 1.432255 Down
Guanine 3.14 × 10−6 8.59 × 10−7 0.273076 −2.29488 0.003089 1.397046 Down
Stachydrine 0.001707 0.000566 0.331413 −1.62896 0.00725 1.344179 Down
Cyclopentylglycine 0.00018 8.12 × 10−5 0.45202 −0.841 0.009717 1.290841 Down
1-Methylpiperidine-2-carboxylic acid 0.00018 8.12 × 10−5 0.45202 −0.841 0.009717 1.290841 Down
C vs B Name B_Mean C_Mean Fold_change log2FC P value VIP Regulated
N-Arachidene glycine 6.96 × 10−7 1.72 × 10−6 2.471037 1.177458 0.007508 2.355552 Up
7-Ketolithocholic acid 3.75 × 10−5 0.000211 5.633176 1.875363 0.026005 2.005959 Up
12-Ketolithocholic acid 3.75 × 10−5 0.000211 5.633176 1.875363 0.026005 2.005959 Up
Apocholic acid 3.75 × 10−5 0.000211 5.633176 1.875363 0.026005 2.005959 Up
d-Mannose 6-phosphate 6.38 × 10−6 1.44 × 10−5 2.257515 0.996863 0.022986 2.014334 Up
2-Furoylglycine 3.49 × 10−6 7.17 × 10−6 2.056719 1.132398 0.00245 2.216046 Up
Gly-Val 5.12 × 10−6 2.15 × 10−6 0.420746 −0.50897 0.042666 1.278769 Down
2-Hydroxy-6-aminopurine 2.49 × 10−6 8.59 × 10−7 0.344707 −1.4607 0.031704 1.483084 Down
Guanine 2.49 × 10−6 8.59 × 10−7 0.344707 −1.4607 0.031704 1.483084 Down

3.5 Metabolic pathway analysis of potential metabolites

Metabolic pathway enrichment analysis was carried out using the KEGG database. Due to the deficiency of vitamin D in the C group, we focused on the metabolic pathways in the C vs B and C vs A groups. Differentially expressed metabolites in the C vs B group were mainly involved in the lysosome, amino sugar and nucleotide sugar metabolism, fructose and mannose metabolism and purine metabolism (Figure 4a). Differentially expressed metabolites in the C vs A group were mainly related to fructose and mannose metabolism, amino sugar and nucleotide sugar metabolism, ABC transporters and galactose metabolism (Figure 4b).

Figure 4 Analyses of metabolic pathways. (a) KEGG pathway analyses of the differential metabolites in C vs B. (b) KEGG pathway analyses of the differential metabolites in C vs A. Each point represents one metabolic pathway. The size of the dots indicates the number of metabolites. Circle colours indicate pathway enrichment significance.
Figure 4

Analyses of metabolic pathways. (a) KEGG pathway analyses of the differential metabolites in C vs B. (b) KEGG pathway analyses of the differential metabolites in C vs A. Each point represents one metabolic pathway. The size of the dots indicates the number of metabolites. Circle colours indicate pathway enrichment significance.

4 Discussion

Vitamin D has a variety of biological functions, including anti-oxidation, anti-inflammation, blood pressure control, immune regulation, apoptosis inhibition and anti-angiogenesis [17,18,19,20]. Some studies demonstrated that 25(OH)D can be significantly reduced in pre-type 2 diabetes mellitus, and the regulation of 1,25(OH)2D3 on oxidative stress is dependent on plasma glucose concentration [21,22]. In this study, we found that 46.67% of people with 25(OH)D ≥40 ng/mL were diagnosed with prediabetes, 86.67% of people with 30–40 ng/mL of 25(OH)D were diagnosed with prediabetes or diabetes, and all people with 25(OH)D <30 ng/mL were diagnosed with prediabetes or diabetes. At the same time, with the decrease of 25(OH)D concentration, HbA1c, FBG, FINS, TXNIP and HOMA-IR were increased, whereas HOMA-β was decreased. These results confirm that vitamin D reduction was closely related to blood glucose disorder, pancreatic β cell secretion disorder and insulin resistance.

In the present study, we found that the levels of TC and LDL were increased with a decrease in 25(OH)D concentration. Cholesterol is essential to all cell membranes and exists inside and outside cells. Lipoprotein particles transport cholesterol and other non-polar substances in plasma [23]. LDL consists of cholesterol, protein and phospholipid shell. It is the leading carrier of cholesterol in peripheral tissues. Its components are easily oxidised to produce oxidised LDL [24]. 7-Ketone cholesterol is the most abundant oxysterol in oxidised LDL, which can repress the rate-limiting step in bile acid biosynthesis and strongly suppress the rate-limiting enzyme HMG-CoA reductase in cholesterol biosynthesis [25,26,27]. It is an endogenous regulator of cholesterol biosynthesis. These results suggested that the 25(OH)D concentration decrease was closely related to cholesterol metabolism disorder.

In this study, we discovered that the expression of bile acid metabolites, such as 7-ketodeoxycholic acid, 7-ketolithocholic acid, 12-ketolithocholic acid and apocholic acid, was significantly upregulated when 25(OH)D was less than 30 ng/mL. Bile acids are synthesised by cholesterol in liver parenchymal cells through a classical pathway intervened by cholesterol 7α -hydroxylase (CYP7A1) and an alternate pathway intervened by sterol 27-hydroxylase (CYP27A1). At least 75% of bile acids are produced by the classical pathway under normal conditions. Deoxycholic acid and chenodeoxycholic acid strongly induce 7α- and 7β-hydroxysteroid dehydrogenase to mediate bile metabolism [28]. Elevated lithocholic acid levels during cholestasis were thought to cause liver damage by inducing apoptotic cell death [29]. Over-physiological dose of lithocholic acid can lead to oxidative stress and DNA damage and induce apoptosis of hepatocytes and colonic epithelial cells. Apocholic acid is a dehydrated product of cholic acid and has carcinogenic activity [30]. As a ligand of G protein-coupled receptor, such as TGR5, cholic acid can regulate its synthesis and hepatoenteric recycling and the homeostasis of TG, cholesterol, energy and glucose [31]. Our findings suggested that the disorder of glucose and lipid metabolism and insulin resistance made the bile acid metabolism in the liver overload and further aggravated the oxidative stress of the liver.

Primary bile acids produced by the liver combine with glycine to form conjugated bile acids [32]. In our study, we discovered that hexanoyl glycine, N-arachidene glycine, apocholic acid, 2-furoylglycine and d-mannose-6-phosphate were significantly upregulated, and cyclopentylglycine, Gly-Val and 2-hydroxy-6-aminopurine were significantly downregulated when 25(OH)D was under 30 ng/mL, which were closely associated with bile acid metabolism. The abnormal expression of these glycine derivatives was closely related to cholesterol metabolism.

Cholesterol can be oxidised in the skin to 7-dehydrocholesterol (7DHC), which is converted to vitamin D3 by ultraviolet irradiation. Ultraviolet irradiation reduced the expression of 7-dehydrocholesterol reductase (DHCR7), which converted 7DHC into cholesterol. CYP27A1, CYP2R1 and CYP27B1 are critical enzymes in active vitamin D synthesis. Ultraviolet irradiation could significantly upregulate CYP27B1 and promote the synthesis of 1α,25(OH)2D3 [33]. CYP2R1 mRNA dramatically declined in the liver of mice fed with high-fat diet [34]. Therefore, the decrease in 25(OH)VD levels in people with abnormal glucose metabolism in our study may be related to the upregulation of DHCR7 and downregulation of CYP27B1 in the body under the condition of excessive energy load, which leads to vitamin D synthesis disorder and further aggravates oxidative stress and chronic inflammation.

The current study had several limitations. We just analysed the clinical characteristics and compared the differential metabolites and related pathways in people with different vitamin D levels using UPLC-MS/MS. We discovered that the disorder of vitamin D metabolism might be associated with cholesterol metabolism and bile acid biosynthesis. However, there is a lack of validation of differential metabolites involved in these processes. In addition, the potential mechanism of abnormal vitamin D metabolism was not further investigated via in vitro and in vivo experiments. Our findings can guide future research in abnormal vitamin D metabolism.

In conclusion, we performed a serum metabolic profiling study in people with different levels of vitamin D. A total of seven, 34 and nine differential metabolites were identified in B vs A, C vs A and C vs B groups, respectively. Moreover, 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid, N-arachidene glycine and d-mannose 6-phosphate were associated with cholesterol metabolism and bile acid biosynthesis. This study will lay the foundation for further research on vitamin D metabolism.

# Equal contributors.

Acknowledgments

Not applicable.

  1. Funding information: This study was supported by Science and Technology benefit program of Ningxia Hui Autonomous Region in 2022 (2022CMG03031), Local science and technology development special projects under the guidance of Ningxia Department of Science and Technology [(2019) No. 49] and Ningxia Natural Science Foundation (2022AAC03732).

  2. Conflict of interest: The authors declare that there is no conflict of interest.

  3. Data availability statement: The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-07-04
Revised: 2023-01-14
Accepted: 2023-01-14
Published Online: 2023-03-01

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
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  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
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  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
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  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0658
Keywords for this article
metabolomics; ultra-high-performance liquid chromatography-tandem mass spectrometry; vitamin D; cholesterol metabolism
Creative Commons
BY 4.0

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  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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